JPS62169791A - Pyrrolo(1, 2-a)(4, 1)benzoxazepine derivative - Google Patents
Pyrrolo(1, 2-a)(4, 1)benzoxazepine derivativeInfo
- Publication number
- JPS62169791A JPS62169791A JP62009181A JP918187A JPS62169791A JP S62169791 A JPS62169791 A JP S62169791A JP 62009181 A JP62009181 A JP 62009181A JP 918187 A JP918187 A JP 918187A JP S62169791 A JPS62169791 A JP S62169791A
- Authority
- JP
- Japan
- Prior art keywords
- formula
- lower alkyl
- formulas
- tables
- halogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- NTTCPWNFMUXMMI-UHFFFAOYSA-N 1,6-dihydropyrrolo[1,2-a][4,1]benzoxazepine Chemical class O1CC2=CC=CC=C2N2CC=CC2=C1 NTTCPWNFMUXMMI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 82
- 239000001257 hydrogen Substances 0.000 claims abstract description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 37
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 35
- 150000003839 salts Chemical class 0.000 claims abstract description 33
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 21
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 21
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims abstract description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims abstract description 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract 17
- 150000002367 halogens Chemical class 0.000 claims abstract 17
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims abstract 3
- -1 pyrrolidino, piperidino Chemical group 0.000 claims description 28
- 238000000034 method Methods 0.000 claims description 24
- 239000000126 substance Substances 0.000 claims description 20
- 239000000203 mixture Substances 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical group NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000004083 gastrointestinal agent Substances 0.000 claims description 2
- 229940125695 gastrointestinal agent Drugs 0.000 claims description 2
- 238000006268 reductive amination reaction Methods 0.000 claims description 2
- 239000003793 antidiarrheal agent Substances 0.000 claims 1
- 229940125714 antidiarrheal agent Drugs 0.000 claims 1
- 241000124008 Mammalia Species 0.000 abstract description 6
- 238000011282 treatment Methods 0.000 abstract description 3
- 102000000584 Calmodulin Human genes 0.000 abstract 1
- 108010041952 Calmodulin Proteins 0.000 abstract 1
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract 1
- 239000005557 antagonist Substances 0.000 abstract 1
- 239000002253 acid Substances 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 14
- 230000002829 reductive effect Effects 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000002904 solvent Substances 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- 238000002360 preparation method Methods 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 10
- 239000007858 starting material Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 230000002496 gastric effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 9
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 238000009835 boiling Methods 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 238000009833 condensation Methods 0.000 description 5
- 230000005494 condensation Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 239000008101 lactose Substances 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- FJKROLUGYXJWQN-UHFFFAOYSA-N 4-hydroxybenzoic acid Chemical compound OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 4
- 206010012735 Diarrhoea Diseases 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000005907 alkyl ester group Chemical group 0.000 description 4
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 4
- 230000001142 anti-diarrhea Effects 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 238000006722 reduction reaction Methods 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 208000025865 Ulcer Diseases 0.000 description 3
- 230000009858 acid secretion Effects 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001408 amides Chemical group 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 230000018044 dehydration Effects 0.000 description 3
- 238000006297 dehydration reaction Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000000543 intermediate Substances 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 231100000397 ulcer Toxicity 0.000 description 3
- ZCXLTWVZYXBHJS-UHFFFAOYSA-N 1,2-benzoxazepine Chemical class O1N=CC=CC2=CC=CC=C12 ZCXLTWVZYXBHJS-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
- 238000007126 N-alkylation reaction Methods 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 229960000212 aminophenazone Drugs 0.000 description 2
- 230000001262 anti-secretory effect Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
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- 239000003085 diluting agent Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 2
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- 238000010438 heat treatment Methods 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
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- 238000001727 in vivo Methods 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 150000002688 maleic acid derivatives Chemical class 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
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- 150000007530 organic bases Chemical class 0.000 description 2
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- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WLXGQMVCYPUOLM-UHFFFAOYSA-N 1-hydroxyethanesulfonic acid Chemical compound CC(O)S(O)(=O)=O WLXGQMVCYPUOLM-UHFFFAOYSA-N 0.000 description 1
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- FZZMTSNZRBFGGU-UHFFFAOYSA-N 2-chloro-7-fluoroquinazolin-4-amine Chemical compound FC1=CC=C2C(N)=NC(Cl)=NC2=C1 FZZMTSNZRBFGGU-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- APIXJSLKIYYUKG-UHFFFAOYSA-N 3 Isobutyl 1 methylxanthine Chemical compound O=C1N(C)C(=O)N(CC(C)C)C2=C1N=CN2 APIXJSLKIYYUKG-UHFFFAOYSA-N 0.000 description 1
- BYNBAMHAURJNTR-UHFFFAOYSA-N 3-piperidin-4-yl-1h-benzimidazol-2-one Chemical compound O=C1NC2=CC=CC=C2N1C1CCNCC1 BYNBAMHAURJNTR-UHFFFAOYSA-N 0.000 description 1
- 229940090248 4-hydroxybenzoic acid Drugs 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- XXRCUYVCPSWGCC-UHFFFAOYSA-N Ethyl pyruvate Chemical compound CCOC(=O)C(C)=O XXRCUYVCPSWGCC-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 206010020601 Hyperchlorhydria Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical group [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 1
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 235000009037 Panicum miliaceum subsp. ruderale Nutrition 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical class [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical compound [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 description 1
- DNEHKUCSURWDGO-UHFFFAOYSA-N aluminum sodium Chemical compound [Na].[Al] DNEHKUCSURWDGO-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000005349 anion exchange Methods 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- 239000003855 balanced salt solution Substances 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Substances OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N beta-hydroxyethanesulfonic acid Natural products OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000022185 broomcorn panic Species 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 235000011089 carbon dioxide Nutrition 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 238000005341 cation exchange Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 239000002024 ethyl acetate extract Substances 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 229940117360 ethyl pyruvate Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- ULITUPMHIDVLLV-UHFFFAOYSA-N formonitrile;sodium Chemical compound [Na].N#C ULITUPMHIDVLLV-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229960001340 histamine Drugs 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910000043 hydrogen iodide Inorganic materials 0.000 description 1
- 229940071870 hydroiodic acid Drugs 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- 150000004692 metal hydroxides Chemical class 0.000 description 1
- 229940102398 methyl anthranilate Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- KIWUVOGUEXMXSV-UHFFFAOYSA-N rhodanine Chemical compound O=C1CSC(=S)N1 KIWUVOGUEXMXSV-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013223 sprague-dawley female rat Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は式Ｉで表わされる新規な４Ｈ，６Ｈ−ピロロ［
１，２−ａ〕［４，１：］ベンゾオキサゼピン誘導体、
その製造方法、該化合物を含む医薬組成物、医薬組成物
の製造の為の該化合物の使用並びにその医薬としての適
用に関する。Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a novel 4H,6H-pyrrolo[
1,2-a][4,1:]benzoxazepine derivative,
The present invention relates to a method for producing the compound, a pharmaceutical composition containing the compound, the use of the compound for producing a pharmaceutical composition, and its application as a medicine.
本発明は次式■：
以下余白
（式中、ｎは整数１．２．３又は４であり；Ｒ１は水素
、低級アルキル、八日ｒン、トリフルオロメチル、ヒド
ロキシもしくは低級アルコキシを表わし；Ｒ２は水素又
は低級アルキルを表わし；Ｒ３は水素、低級アルキル又
は八日ｒンを表わし；Ｒ４はアミノ、低級アルキルアミ
ノ、ノー低級アルキルアミノ、モルホリノ、Ｎ−低級ア
ルキルもしくはＮ−アリールーピベラソノ、ピロリジノ
、ピペリジノ又は
素、−・口ｒン又は低級アルキルを表わす）から選ばれ
る置換ピペリジノを表わす）
で表わされる４−置換−４Ｈ，６Ｈ−ピロロ−（１，２
−ａ〕（４，１）ベンゾオキサゼピン誘導体およびその
塩に関したものである。The present invention is based on the following formula: represents hydrogen or lower alkyl; R3 represents hydrogen, lower alkyl or hydrogen; R4 represents amino, lower alkylamino, no-lower alkylamino, morpholino, N-lower alkyl or N-aryl piberazono, pyrrolidino 4-substituted-4H,6H-pyrrolo-(1,2
-a](4,1) benzoxazepine derivatives and salts thereof.
特に興味がある化合物は、次式■ 以下余白 （式中Ｒ１は水素、低級アルキル、・）口ｒン。The compound of particular interest is the following formula■ Margin below (In the formula, R1 is hydrogen, lower alkyl, etc.).
トリフルオロメチル、ヒドロキシ又は低級アルコキシを
表わし；Ｒ２は水素又は低級アルキルを表わし：ｎは整
数１〜４を表わし；更にＲ６は水素。represents trifluoromethyl, hydroxy or lower alkoxy; R2 represents hydrogen or lower alkyl; n represents an integer from 1 to 4; and R6 represents hydrogen.
ハロゲノ又は低級アルキルを表わす）
で表わされる化合物及びその医薬として許容され得る塩
である。(representing halogeno or lower alkyl) and pharmaceutically acceptable salts thereof.
更に好ましい化合物は式■（式中、ｎは整数１又は２で
あり；Ｒ２は直鎖の低級Ｃ１〜４アルキルであり：Ｒ１
及びＲ５は水素又は・・口ｒンである）で表わされる化
合物及びその医薬として許容され得る塩である。A more preferred compound is a compound of the formula (1) (wherein n is an integer 1 or 2; R2 is a linear lower C1-4 alkyl; R1
and R5 is hydrogen or...) and pharmaceutically acceptable salts thereof.
特に好ましい化合物は、式■（式中Ｒ１及び ・Ｒ５が
水素であり、Ｒ２がメチル又はエチルであリ；及びｎが
整数１である）である化合物及びその医薬として許容さ
れ得る塩である。Particularly preferred compounds are compounds of the formula (1) in which R1 and .R5 are hydrogen, R2 is methyl or ethyl; and n is an integer 1, and pharmaceutically acceptable salts thereof.
本発明で用いられる一般的定義は本発明の範囲内におい
て次の意味を有する。The general definitions used in this invention have the following meaning within the scope of this invention.
ハロダンは、好ましくは塩素及びフッ素であるが、臭素
又はヨウ素であってもよい。Halodane is preferably chlorine and fluorine, but may also be bromine or iodine.
語句「低級」は有機基又は化合物のそれぞれに関し先に
或いは後に定義されるものに言及し炭素原子数７まで及
び７を含むものを意味し、好ましくは４まで更に４を含
み更に好都合には１個又は２個の炭素原子を意味する。The term "lower" refers to organic radicals or compounds as defined above or below, respectively, and means up to and containing 7 carbon atoms, preferably up to and including 4 and more conveniently 1. or 2 carbon atoms.
低級アルキルは１〜７個の炭素原子を含有し、好ましく
は１〜４個の炭素原子を含有し、これは好都合には直鎖
であり、例えばメチル、エチル、プロピル又はブチル、
好都合にはメチルでおる。Lower alkyl contains 1 to 7 carbon atoms, preferably 1 to 4 carbon atoms, and is conveniently straight chain, for example methyl, ethyl, propyl or butyl,
Conveniently methyl.
低級アルコキシは好ましくは直鎖のＣ１〜４アルコキシ
であり、例えばメトキシ、エトキシ、プロポキシ、好都
合にはメトキシである。Lower alkoxy is preferably straight-chain C1-4 alkoxy, such as methoxy, ethoxy, propoxy, conveniently methoxy.
アリールは好ましくはフェニル又は低級アルキルもしく
はハロダンによりモノ置換されたフェニルである。Aryl is preferably phenyl or phenyl monosubstituted by lower alkyl or halodane.
医薬として許容され得る塩は、酸付加塩であり、これは
好ましくは例えば医薬として許容され得る無機もしくは
有機酸、例えば強鉱酸、例えばヒドロハロゲン僚、例え
ば塩酸もしくは臭酸；スルホン酸、燐酸もしくは硝酸；
脂肪族もしくは芳香族スルホン酸、例えばメタンスルホ
ン酸、エタンスルホン酸、ヒドロキシェタンスルホン酸
、ベンゼンスルホン酸、ｐ−トルエンスルホン酸モしく
はナフタレンスルホン酸、脂肪族もしくは芳香族カルが
ン酸、例えば、酢酸、プロピオン酸、コハク酸、ゲルコ
ール酸、乳酸、リンゴ酸、酒石酸、グルコン酸、クエン
酸・マレイン酸、フマール酸、ヒルヒン酸、フェニル酢
酸、安息香酸、４−アミ７安息香酸、アントラニル酸、
４−ヒドロキシ安息香酸、サリチル酸、４−アミンサリ
チル酸、パモイック酸、ニコチン酸又はアスコルビン酸
である。Pharmaceutically acceptable salts are acid addition salts, which are preferably acid addition salts, for example with pharmaceutically acceptable inorganic or organic acids, such as strong mineral acids, such as hydrohalogen compounds, such as hydrochloric acid or hydrobromic acid; sulfonic acid, phosphoric acid or nitric acid;
Aliphatic or aromatic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, aliphatic or aromatic carboxylic acids, e.g. , acetic acid, propionic acid, succinic acid, gelcholic acid, lactic acid, malic acid, tartaric acid, gluconic acid, citric acid/maleic acid, fumaric acid, hiruhic acid, phenylacetic acid, benzoic acid, 4-ami7benzoic acid, anthranilic acid,
4-hydroxybenzoic acid, salicylic acid, 4-amine salicylic acid, pamoic acid, nicotinic acid or ascorbic acid.
本発明の化合物は、価値ある薬理作用、例えば、哺乳動
物におけるコルモジュリン作用を阻止することによる胃
腸の抗分泌作用、特に抗下痢作用を示す。The compounds of the invention exhibit valuable pharmacological effects, such as gastrointestinal antisecretory, especially antidiarrheal, effects by blocking colmodulin action in mammals.
この作用は試験管内並びに試験対象物として例えばマウ
ス、ラット又はイヌの如き動物を好都合により用いて生
体内試験で実証される。この化合物は例えばゼラチンカ
プセル内で文は水溶液もしくは懸濁液の形態で前記動物
に経腸的に又は非経口的に、好都合には経口的に、皮下
的に、静脈内もしくは腹腔内的に投与することが出来る
。投与量は約０．１０〜１００吟へＶ日、好ましくは約
０．５０〜５０１ｖ／に９／日、好都合には５〜３０■
／Ｖ日 である。試験管内での適用量は約１０〜１０”
” Ｍ濃度、好ましくは約ｌＯ〜１０ Ｍである。This effect is demonstrated in vitro as well as in vivo tests, conveniently using animals such as mice, rats or dogs as test subjects. The compound is administered to the animal enterally or parenterally, conveniently orally, subcutaneously, intravenously or intraperitoneally, in the form of an aqueous solution or suspension, for example in a gelatin capsule. You can. The dosage is about 0.10 to 100 V/day, preferably about 0.50 to 501 V/day, conveniently 5 to 30 V/day.
/V day. The amount applied in vitro is approximately 10-10”
”M concentration, preferably about 10 to 10M.
該新規化合物の抗下痢作用を表わすコルモジュリン阻害
作用は、Ｊ、Ａ、ノーマン等（Ｍｏｌ。The colmodulin inhibitory action, which represents the anti-diarrheal action of the new compound, was reported by J. A. Norman et al. (Mol.
Ｐｈａｒｍａｅｏｌｏｇｙ １６ 、１０８９（１９７
９） ）による方法に従い、ウシｃ −ＡＭＰホスホ
ソエステラーゼのコルモジュリン誘起活性の阻害を測定
することにより試験管内で測定される。Pharmaeology 16, 1089 (197
9) It is determined in vitro by measuring the inhibition of colmodulin-induced activity of bovine c-AMP phosphosoesterase according to the method described in (9)).
本発明の例示である、１．３−ジヒドロ−１−（１−（
（４−メチル−４Ｈ，６Ｈ−ピロロ［：１．２−ａ〕（
４，１）ベンゾオキサゼピン−４−イル）−メチルツー
４−ピペリジニル）−２Ｈ−ベンズイミダゾール−２−
オンマレエートハ、試験管内でホスホジェステラーゼの
コルモジュリン誘起活性を、約３ Ｘ １０−’モルの
濃度で５０チだけ抑制する。1,3-dihydro-1-(1-(
(4-methyl-4H,6H-pyrrolo[:1.2-a](
4,1) Benzoxazepin-4-yl)-methyl-4-piperidinyl)-2H-benzimidazole-2-
Onmaleate inhibits the colmodulin-induced activity of phosphogesterase in vitro by a factor of 50 at a concentration of about 3 x 10-' molar.
本発明化合物の抗下痢作用は、プロスタグ腹腔ジンＥ２
ヲ腹腔内投与することにより・ラットに誘起した下痢を
抑制する程度を測定することにより行われる。The anti-diarrheal effect of the compound of the present invention is due to prostag peritoneal gin E2.
This is done by intraperitoneal administration and by measuring the degree of suppression of diarrhea induced in rats.
試験は次の如く行なう：
体重２００〜２５０ｇを有しかつ１８時間絶食せしめた
雌のスプラーグードーレイ種のラットｔ−用いる。試験
化合物を、水で３０〜５０％ジメチルスルホキシド濃度
に希釈したジメチルスルホキシドに溶解し、次いで１
ｄ／に９の容量で胃洗浄に工す経口的に投与した。３０
分もしくは６０分後、ゾロスタグランソンＥ２（１５０
μｇ ）を、０．５１Ｌｌの水の容量で投与する（＋、
ｐ、）。未処理動物に比較した排便の減少を、プロスタ
グランジンＥ２ の投与後３０分間測定する。The test is carried out as follows: Female Sprague-Dawley rats weighing 200-250 g and fasted for 18 hours are used. Test compounds were dissolved in dimethyl sulfoxide diluted with water to a 30-50% dimethyl sulfoxide concentration, then 1
It was administered orally for gastric lavage at a volume of 9 mg/day. 30
minutes or 60 minutes later, Zorostagranson E2 (150
μg) is administered in a volume of 0.51 Ll of water (+,
p,). The reduction in defecation compared to untreated animals is measured 30 minutes after administration of prostaglandin E2.
本発明の例示である、１，３−ジヒドロ−１−（１−［
：（４−メチル−４Ｈ，６Ｈ−ピロロ［１，２−ａ）（
：４．１１ベンゾオキサゼピン−４−イル）−メチル〕
−４−ピペリジニル）−２Ｈ−ベンズイミダゾール−２
−オンマレエートハラットにおいて１０■／ゆの用量（
ｐ、Ｏ，）でプロスタグランジンＥ２ 誘発排便を減少
せしめる。Exemplifying the present invention, 1,3-dihydro-1-(1-[
:(4-methyl-4H,6H-pyrrolo[1,2-a)(
:4.11benzoxazepin-4-yl)-methyl]
-4-piperidinyl)-2H-benzimidazole-2
- a dose of 10 μ/yu in onmaleate halat (
p, O,) reduces prostaglandin E2-induced defecation.
抗潰瘍作用を示す酸の分泌の抑制は、次の如くラットの
胃壁細胞内で生体内で測定出来る：約Ｉ Ｘ １０’個
の胃壁細胞（１８〜２２％増）を、グルコース、ＢＳＡ
（ウシ自消アルブミン）、０．１ｐｃｌの１４Ｃ−アミ
ノピリン、ヒスタミン（１ｍＭ）、イソブチルメチルキ
サンチン（０，１ｍＭ ）及び被験化合物を含有する平
衡塩溶液中、３７℃で９５％酸素のもと、４０分間イン
キュベートする。次いで細胞を洗浄し、蒸留水で破壊し
次いでシンチレーションスペクトロメーターにエリ分析
する。Inhibition of acid secretion, which exhibits anti-ulcer properties, can be measured in vivo in rat gastric parietal cells as follows: about I x 10' gastric parietal cells (18-22% increase) are treated with glucose, BSA,
(bovine self-extinguishing albumin), 0.1 pcl of 14C-aminopyrine, histamine (1mM), isobutylmethylxanthine (0.1mM) and the test compound in a balanced salt solution at 37°C under 95% oxygen. Incubate for minutes. Cells are then washed, disrupted with distilled water and analyzed in a scintillation spectrometer.
細胞内の Ｃ−アミノピリンの蓄積の減少は、酸の分泌
を抑制する間接測定を表わす。A decrease in intracellular C-aminopyrine accumulation represents an indirect measure of inhibiting acid secretion.
本発明の例である、１．３−ジヒドロ−１−（１−［（
４−メチル−４Ｈ，６Ｈ−ピロロ［１，２−ａ〕（４，
１）ベンゾオキサゼピン−４−イル）−メチル〕−４−
ピペリジニル）−２Ｈ−ペンズイミダゾール−２−オン
マレエートハ、工Ｃ５ｏが約３Ｘ１０ Ｍを示す、ラ
ットの胃壁における酸分泌を抑制する。Examples of the present invention, 1,3-dihydro-1-(1-[(
4-Methyl-4H,6H-pyrrolo[1,2-a](4,
1) Benzoxazepin-4-yl)-methyl]-4-
(piperidinyl)-2H-penzimidazol-2-one maleate, exhibiting approximately 3×10 M of C5o, inhibits acid secretion in the gastric wall of rats.
従って、本発明の化合物は胃腸剤、例えば胃腸の抗分泌
剤、例えば下痢、潰瘍、胃酸過多、腸の炎症疾患及び脱
水症状の治療又は管理に対し有用である。Accordingly, the compounds of the present invention are useful for gastrointestinal agents, such as gastrointestinal antisecretory agents, such as for the treatment or management of diarrhea, ulcers, gastric hyperacidity, intestinal inflammatory diseases and dehydration conditions.
本発明の化合物、即ち式ｌ又は式■の化合物及びそれ等
の塩は、次の方法に従って好ましく調製される：
＆）次式■：
Ｒ４−Ｈ（ｍ）
（式中、Ｒ４は特許請求の範囲第１項で定義した意味と
同じであり、さらに水素は鉄基Ｒ４のアミノ窒素に結合
している）
で表わされるアミンを、次式■：
町
（式中、ｎ ｅ Ｒ１＊ Ｒ２およびＲ３は特許請求の
範囲第１項で定義した意味と同じであり、さらにＸは反
応性エステル化ヒドロキシを表わす）で聚わされる化合
物と縮合させるか、又は次式■：（式中、ｎ ｓ Ｒ１
＋ Ｒ２お工びＲ５は先に定義した意味と同じである）
で表わされる化合物と還元的アミノ化の条件下で縮合さ
せるか、又は
ｂ）次式■：
（式中、ｎおよびＲ１−Ｒ４は特許請求の範囲第１項で
定義した意味と同じである）
で表わされる化合物を還元し；次いで前記シーセスを行
い、この間必要力らば全てのこれらのプロセス中防害性
反応基を保護し、次いで得られた式ｌの化合物を本発明
の他の化合物に変換し、および／又は所望により得られ
た遊−化合物を塩に変換するか又は得られた塩を遊離化
合物もしくは他の塩に変換するか、お工び／又は、所望
により得られた異性体又はラセミ体混合物を個々の異性
体又はラセミ体に分野し、および／又は得られたうセミ
体を光学対掌体に分割する。The compounds of the present invention, i.e. compounds of formula l or formula (■) and salts thereof, are preferably prepared according to the following method: &) Formula (2): R4-H(m), where R4 is The amine represented by the following formula (has the same meaning as defined in Range 1, and in addition hydrogen is bonded to the amino nitrogen of the iron group R4): has the same meaning as defined in claim 1, and furthermore, X represents a reactive esterified hydroxyl, or is condensed with a compound of the following formula ■: (where n s R1
+ R2 and R5 have the same meaning as defined above) or b) condensation with a compound of the following formula ■: (wherein n and R1-R4 has the same meaning as defined in claim 1); then the above-mentioned sheathing is carried out, and during this process, if necessary, all the harmful reactive groups are protected during these processes. , then converting the obtained compound of formula I into other compounds of the invention and/or optionally converting the obtained free compound into a salt or converting the obtained salt into the free compound or other salts. converting or processing/or optionally dividing the resulting isomer or racemic mixture into individual isomers or racemates and/or resolving the resulting racemate into its optical antipodes. .
上記プロセスにおける反応性エステル化ヒドロキシ基は
、強酸、特に強無機酸、例えば・・ロダン什水素酸、特
に塩化水素酸、臭化水素酸又はヨウ化水素酸又は硫酸、
又は強有機酸、特に強有機スルホン酸、例えば脂肪族も
しくは芳香族スルホ７１１．例りばメタンスルホン酸、
４−メチルフェニルｘルホｙ酸もＬ＜ｕ４− ブロモフ
ェニルスルホン酸を用いてエステル化されたヒドロキシ
である。The reactive esterified hydroxy group in the above process is a strong acid, especially a strong inorganic acid, such as rhodanic acid, especially hydrochloric acid, hydrobromic acid or hydroiodic acid or sulfuric acid,
or strong organic acids, especially strong organic sulfonic acids, such as aliphatic or aromatic sulfonants. For example, methanesulfonic acid,
4-Methylphenylxsulfoic acid is also hydroxy esterified with L<u4-bromophenylsulfonic acid.
該反応性エステル化ヒＦロキシ基は、特に・・口、例え
ばクロロ、プロそもしくはヨードであるか、又は脂肪族
もしくは芳香族置換スルホニルオキシ、ＰＩ ｊ ハフ
ェニルスルホニルオキシもしく１ｄ４−メチルフェニル
スルホニルオキシ（トシルオキシ）である。The reactive esterified hydroxy group is in particular... eg chloro, proso or iodo, or an aliphatic or aromatic substituted sulfonyloxy, PI j haphenylsulfonyloxy or 1d4-methylphenylsulfonyl Oxy (tosyloxy).
本明細書中で説明する方法により本発明化合物に変換さ
れる出発化合物もしくは中間体において、ホルミル、カ
ル？キシ、アミノもしくはヒドロキシ基の如き存在する
官能基は、所望により有機合成化学において周知である
通常の保護基により保護される。保護されたホルミル、
カルがキシ、アミノもしくはヒドロキシ基は、温和な条
件下で分子構造が破壊されもしくは他の好ましくない副
作用が生起することなく遊離のホルミル゛、カルがキシ
、アミノ及びヒドロキシ基に変換出来る基である。In the starting compounds or intermediates that are converted to compounds of the invention by the methods described herein, formyl, cal? Functional groups present such as xy, amino or hydroxy groups are optionally protected by conventional protecting groups well known in synthetic organic chemistry. protected formyl,
A carboxy, amino or hydroxy group is a group that can be converted into a free formyl, carboxy, amino or hydroxy group under mild conditions without destroying the molecular structure or causing other undesirable side effects. .
保護基を導入する目的は、反応成分と好ましくない反応
から、更に好ましい化学的変換を行う為に使用される条
件下で官能基を保護することにある。特定の反応の為の
保護基の必要性及び選択は、当業者に周知でありこれは
保護すべき官能基（カルがニル基、カルがキシ基、アミ
ノ基等）の性質に依存し、置換基がその一部をなす分子
の構造及び安定性、並びに反応条件に依存する。The purpose of introducing a protecting group is to protect the functional group from undesired reactions with the reactants under the conditions used to further carry out the desired chemical transformation. The necessity and selection of protecting groups for a particular reaction is well known to those skilled in the art and depends on the nature of the functional group to be protected (cal-nyl, cal-oxy, amino, etc.) It depends on the structure and stability of the molecule of which the group is a part and on the reaction conditions.
これ等の条件及びこれ等の導入及び除去に合致する周知
の保護基は、例えばＪ、Ｆ、Ｗ、マツクオミーにおける
ｓ ｒ Ｐｒｏｔｓｅｔｉｖｓ Ｇｒｏｕｐｓ ｉｎＯ
ｒｇａｎｉｃ Ｃｈｅｍｉｓｔｒｙ Ｊ （プレナムゾ
レス、ロンドン、ニューヨーク１９７３）、Ｔ、Ｗ、グ
リーン、ｒ Ｐｒｏｔｅｃｔｉｖ＠Ｇｒｏｕｐｓ １ｎ
Ｏｒｇａｎｉｃ ５ｙｎｔｈ＠ａｌｓ Ｊ（ワイレイ
、ニューヨーク１９８１）、及びｒ Ｔｈｅ Ｐ＠ｐｔ
ｌｄｅｌＩＪ （１巻、シュレーダー及びリューペック
、アカデミツクプレス、ロンドン、ニューヨーク１９６
５）、並びにノ１ウベンヴエリイにおいてｒ Ｍｅｔｈ
ｏｄｅｎ Ｄｅｒ ＯｒｇａｎｉｓａｔｉｏｎＣｈｅｍ
ｉｅ Ｊ （１５／１巻、ジオーｒシイエーメフィルラ
ーク・スティッフがルト、１９７４）に記載されている
。Well-known protecting groups meeting these conditions and their introduction and removal are described, for example, in J, F, W, s r Protsetivs Groups in O
rganic Chemistry J (Plenum Soles, London, New York 1973), T. W. Green, r Protective@Groups 1n
Organic 5ynth@als J (Wiley, New York 1981), and r The P@pt
ldelIJ (1 volume, Schröder and Luepeck, Academic Press, London, New York 196
5), as well as rMeth
oden Der OrganizationChem
ie J (Vol. 15/1, George Ruto, 1974).
式■の化合物を用いた式■のアミンのＮ−アルキル化を
含むプロセスａ）による本発明の化合物の調製は、常法
により、通常不活性溶剤もしくは不活性溶剤混合物中で
更に所望により、冷却もしくは加熱しながら、例えば約
−２０℃〜約１５０℃の温度−囲で及び／又は不活性ガ
ス雰囲気中で行うことが中米る。反応は好都合−には塩
基、例えば無機塩基、例えばアルカリ金属もしくはアル
カリ土類金属炭酸塩、水素化物もしくは水酸化物、又は
有機塩基１例えばアルカリ金属低級アルコキシド、もし
くは第三アミン例えばトリエチルアミンもしくはピリジ
ンの存在下で行われる。The preparation of the compounds of the invention by process a), which involves N-alkylation of an amine of formula 1 with a compound of formula Alternatively, it may be carried out with heating, for example at a temperature range of about -20°C to about 150°C and/or in an inert gas atmosphere. The reaction is conveniently carried out in the presence of a base, such as an inorganic base such as an alkali metal or alkaline earth metal carbonate, hydride or hydroxide, or an organic base such as an alkali metal lower alkoxide, or a tertiary amine such as triethylamine or pyridine. It takes place below.
還元的Ｎ−アルキル化による、式Ｖのアルデヒドを用い
た弐■のアミノの縮合を含むプロセスａ）による本発明
の調製は、当業者に周知の条件下、例えば白金、パラジ
ウムもしくはニッケル触媒の存在下で水素を用いた接触
水素添加により、又はイ［学的還元剤例えば単純もしく
は錯軽金属水素化物、好都合にはアルカリ金属シアノぎ
口・・イドライド例えばナトリウムシアノぎ口・１イド
ライドを用いて行うことが出来る。アルカリ金属シアノ
？ロバイドライドによる還元的アミン化は、好ｉしくは
不活性溶剤、例えばメタノールもしくはアセトニ） Ｉ
Ｊシル中好都合には酸例えば塩酸もしくは酢酸の存在下
で行われる。The preparation of the invention according to process a), which involves condensation of the amino of 2 with an aldehyde of formula V by reductive N-alkylation, can be carried out under conditions well known to those skilled in the art, for example in the presence of a platinum, palladium or nickel catalyst. by catalytic hydrogenation with hydrogen or with a chemical reducing agent such as a simple or complex light metal hydride, conveniently an alkali metal cyanohydride, such as a sodium cyanohydride. I can do it. Alkali metal cyano? The reductive amination with lobidride is preferably carried out in an inert solvent, such as methanol or acetonyl.
The reaction is conveniently carried out in the presence of an acid such as hydrochloric acid or acetic acid.
アミド官能基が最終生成物に存在する式Ｉの化合物の調
製に対しプロセスａ）が好ましい。Process a) is preferred for the preparation of compounds of formula I in which an amide function is present in the final product.
プロセスｂ）にＬる本発明の化合物の調製は、アミド官
能基の還元に対し当業者に周知の単純もしくは錯水素化
還元剤、例えば不活性溶剤、例えばテトラヒＦロフラン
もしくはジエチルエーテル中すチウムアルミニウム水累
化物もしくはボランを用い、好都合には室温ないし溶剤
沸点近くの温度で還元により好ましく行われる。The preparation of the compounds of the invention according to process b) can be carried out using simple or complex hydrogenated reducing agents well known to those skilled in the art for the reduction of the amide function, such as sodium aluminum in an inert solvent such as tetrahydrofuran or diethyl ether. It is preferably carried out by reduction using a water concentrate or borane, conveniently at room temperature to a temperature near the boiling point of the solvent.
式■の出発物質は公知であるか又は公知でない場合画業
者に周知の方法により調製される。The starting materials of formula (1) are known or, if not known, prepared by methods well known to those skilled in the art.
式■及び式■の出発物質は、当業者に周知の官能基変換
を用いて調製される。Starting materials of formula (1) and formula (2) are prepared using functional group transformations well known to those skilled in the art.
適当に置換されたアントラニル酸のエステルは・例えば
酢酸中加熱しながら２．５−ジー低級アルコキシテトラ
ヒＦロフランと縮合させ、ｏ（１−ピロリル）−安息香
酸エステル、例えば低級アルキルエステルを得、これは
引き続き不活性溶剤中リチウムアルミニウム水素化物を
用いて還元され適当に置換された式■：
（式中、Ｒ１及びＲ３は式■の化合物で定義された意味
を有する）
で表わされるｏ−（１−ピロリル）−イ：／シルフルコ
ールに還元される。Suitably substituted esters of anthranilic acid are condensed with 2,5-di-lower alkoxytetrahyfuran with heating, e.g. in acetic acid, to yield o(1-pyrrolyl)-benzoic acid esters, e.g. lower alkyl esters; This is subsequently reduced using lithium aluminum hydride in an inert solvent and suitably substituted to give an o-( 1-pyrrolyl)-i: reduced to silflucol.
式■：
Ｒ２−Ｃ−（ＣＨ２）ｎ、−ＣＯＯＨ（■）（式中、ｎ
及びＲ２は先に定義した意味である）で表わされる化合
物又はそのエステル、例えば低級アルキルエステルと式
■の化合物との縮合は、好都合には強塩基、例えばブチ
ルリチウムもしくはリチウムジイソプロピルアミドの存
在下で、又は酸、例えば臭化水素酸の存在下で行われた
式■：（式中、ｎ ＋ Ｒ１ｅ Ｒ２及びＲ３は式Ｉの
化合物に対し定義された意味と同じである）
゛で表わされる化合物又はそのエステル、例えば低級ア
ルキルエステルを与える。Formula ■: R2-C-(CH2)n, -COOH(■) (in the formula, n
and R2 have the meaning defined above) or an ester thereof, such as a lower alkyl ester, with a compound of formula (1), conveniently in the presence of a strong base, such as butyllithium or lithium diisopropylamide. , or in the presence of an acid, for example hydrobromic acid, of the formula ■: (wherein n + R1e R2 and R3 have the same meanings as defined for the compounds of formula I) or an ester thereof, such as a lower alkyl ester.
選択的化学還元剤、例えばジイソブチルアルミニウム水
素化物による式■の化合物のエステルの還元は、式Ｖの
アルデヒド中間体を与える。Reduction of the ester of the compound of formula (1) with a selective chemical reducing agent such as diisobutylaluminum hydride provides the aldehyde intermediate of formula V.
カルゼン酸もしくはエステルを対応するアルコールに還
元するのに有効であることが周知の還元剤、例えばジブ
ラン、ナトリウムビス−（２−メトキシ−エトキシ）−
アルミニウム水素化物もしくは水素化アルミニウムリチ
ウムを用いて式■の化合物を還元すると、弐■（式中Ｘ
はヒドロキシである）の化合物を得る。Reducing agents known to be effective in reducing carzene acids or esters to the corresponding alcohols, such as dibran, sodium bis-(2-methoxy-ethoxy)-
When the compound of formula (■) is reduced using aluminum hydride or lithium aluminum hydride,
is hydroxy).
式■（式中Ｘはヒドロキシである）の該化合物は、当業
者に周知の手順を用い、弐■（式中Ｘは先に定義した如
くエステル化ヒドロキシを表わす）の対応する化合物に
変換される。例えば、式■（式中Ｘは・・口例えばクロ
ロもしくはブロモを表わす）の化合物の変換は、塩化チ
オニル又はオキシ塩化燐の如き通常の試剤を用いて行わ
れる。The compound of formula 1 (wherein X is hydroxy) is converted to the corresponding compound of formula 2 (wherein X represents esterified hydroxy as defined above) using procedures well known to those skilled in the art. Ru. For example, the conversion of compounds of formula (1) in which X represents eg chloro or bromo is carried out using conventional reagents such as thionyl chloride or phosphorus oxychloride.
式■の出発物質は、式■のカルぎン酸又はその反応性官
能誘導体を、式Ｉ中の基Ｒ４に対応するアミン、即ち式
Ｒ４−Ｈ（式中Ｒ４は先に定義した意味と同じであり更
にＨは基Ｒ４のアミノ窒素に結合している）の化合物を
用いて、アミド結合の形成に対し当業者に周知の条件の
もとて縮合させることにより得られる。The starting material of formula (II) is a carginic acid of formula (II) or a reactive functional derivative thereof, which is an amine corresponding to the group R4 in formula I, i.e., formula R4-H, where R4 has the same meaning as defined above. and H is bonded to the amino nitrogen of the group R4) by condensation under conditions well known to those skilled in the art for the formation of an amide bond.
先の式■のカルがン酸の反応性官能誘導体は、例えば・
・ログン化アシル例えば酸塩化物、核酸の無水物、混合
無水物例えば低級アルキルハロ炭酸塩から誘導されるも
の例えばクロルギ酸エチル、反応性エステル・例えば低
級アルキルエステル例えばエチルもしくはメチルエステ
ル又は所望により置換されたフェニルエステル、又はア
ミド、例えばイミダゾールから誘導されるもの（Ｎ、Ｎ
−カルがニルジイミダゾールから調製）を表わす。The reactive functional derivative of carganic acid of the above formula ■ is, for example,
eg ethyl chloroformate, reactive esters such as lower alkyl esters such as ethyl or methyl esters or optionally substituted phenyl esters, or amides, such as those derived from imidazole (N, N
- cal is prepared from nyldiimidazole).
置換基の性質に応じて適当に保護された式■（Ｒ４−Ｈ
）のアミンと、遊離カル？ン酸の形態にある式■の化合
物との縮合は、縮合剤例えばジシクロへキシルカルがジ
イミドもしくは１．１′−ジイミダゾリルカルデニル（
カルがニルジイミダゾール）の存在中、不活性溶剤、例
えば塩化メチレンもしくはテトラヒドロフランの溶剤中
、溶剤の沸点付近の温度で好都合に行われる。Formula ■ (R4-H
) amine and free cal? The condensation with a compound of formula (1) in the form of phosphoric acid is carried out when the condensing agent, for example dicyclohexylcal, is diimide or 1,1'-diimidazolylcardenyl
Conveniently, the reaction is carried out in the presence of an inert solvent such as methylene chloride or tetrahydrofuran, in the presence of a compound (nildiimidazole) at a temperature near the boiling point of the solvent.
弐■の化合物と１例えば酸・・ロダン化物好都合には酸
塩化物、又は混合無水物の形態にある式■の酸の反応性
官能誘導体との縮合は、不活性溶剤例えばトルエン又は
塩化メチレンの如き不活性溶剤中、好ましくは塩基、例
えば無機塩基、例えば炭酸カリウム又は有機塩基例えば
トリエチルアミンもしくはピリジンの存在下、約０℃〜
１００’。The condensation of the compound of formula II with a reactive functional derivative of the acid of formula II, such as an acid, preferably in the form of a rhodanide, an acid chloride, or a mixed anhydride, is carried out in an inert solvent such as toluene or methylene chloride. from about 0° C., preferably in the presence of a base, such as an inorganic base such as potassium carbonate or an organic base such as triethylamine or pyridine.
100'.
好ましくは室温で行われる。Preferably it is carried out at room temperature.
上記プロセスにより得られた本発明の化合物は、当業者
に周知の類似方法により式ｌの本発明の他の化合物に変
換出来る。Compounds of the invention obtained by the above process can be converted into other compounds of the invention of formula 1 by analogous methods well known to those skilled in the art.
例えば式■（式中Ｒ１は低級アルコキシである）の化合
物の式■（式中Ｒ１はヒドロキシを表わす）の化合物へ
の変換は、描業者に周知の方法により、例えば鉱酸、例
えばヨウ化水素酸を用いて行われ、或いは好都合には低
級アルコキシがメトキシである化合物に対しては、例え
ば塩化メチレン中？ロントリプロミド又はテトラヒドロ
フラン中すチウムソフェニルホスフィドを用いて行われ
る。For example, the conversion of a compound of formula (1) (in which R1 is lower alkoxy) to a compound of formula (1) (in which R1 represents hydroxy) can be carried out using, for example, mineral acids, such as hydrogen iodide, by methods well known to those skilled in the art. For compounds where the lower alkoxy is conveniently methoxy, for example in methylene chloride? It is carried out using lontripromide or sodium sophenyl phosphide in tetrahydrofuran.
上記の反応は、標準の方法に従い、希釈剤、好ましくは
試剤に不活性であり更にその溶剤であるものの存在もし
くは非存在下、触媒、縮合剤もしくは他の試剤の存在も
しくは非存在下、及び／又は不活性雰囲気中、低温度、
室温又は高温度、好ましくは用いる溶剤の沸点近くの温
度で大気圧又は加圧下で行われる。The above reactions are carried out according to standard methods, in the presence or absence of a diluent, preferably inert to the reagents and also their solvent, in the presence or absence of catalysts, condensing agents or other reagents, and/or or in an inert atmosphere at low temperatures;
It is carried out at room temperature or elevated temperature, preferably at a temperature near the boiling point of the solvent used, at atmospheric pressure or under elevated pressure.
本発明は更に本発明のプロセスの変法を含み、このプロ
セスにおいていかなる工程でも得られる中間生成物は出
発物質として用いられ更に残りの工程が行われ、或いは
又プロセスはその任意の段階で中断され、或いはその段
階において出発物質は反応条件下で形成され、或いはそ
の段階において反応成分がその塩の形態で用いられる。The invention further includes variations of the process of the invention, in which intermediate products obtained at any step in the process are used as starting materials to carry out the remaining steps, or the process is interrupted at any stage thereof. , or in that step the starting materials are formed under the reaction conditions, or in that step the reaction components are used in the form of their salts.
好ましい場合にはいつでも、上記プロセスは先に説明し
た如く或いは実施例で説明する如く強力に妨害する反応
性官能基をまず最初に適当に保饅した後行われる。Whenever preferred, the above process is carried out after first suitably retaining the strongly interfering reactive functional groups as described above or as illustrated in the Examples.
好都合には、これ等の出発物質は、先に好ましいものと
して示された化合物の形成に至らしめる、該反応剤にお
いて用いられるべきである。Conveniently, these starting materials should be used in the reagents leading to the formation of the compounds indicated above as preferred.
最後に本発明の化合物は遊離の形態、又はその塩として
得られる。得られた塩基は、好ましくは医薬として許容
され得る酸又はアニオン交換調製を用いて対応する酸付
加塩に変換出来、或いは得られた塩は例えば強塩基、例
えば金属もしくはアンモニウム水酸化物、又は塩基性塩
、例えばアルカリ金属水酸化物もしくは炭酸塩又はカチ
オン交換調製により変換出来る。これ等の又は他の塩、
例えばピクラートも又得られた塩基の精製に対し用いる
ことが出来る。遊離化合物及びその塩の形態にある化合
物間での近似した関係を考慮すれば、化合物とはこの意
味に関し、対応する塩も又含まれる。但し与えられた環
境のもとてその様なものが可能であるか或いは適当な場
合である。Finally, the compounds of the invention are obtained in free form or as their salts. The resulting base can be converted into the corresponding acid addition salt, preferably using a pharmaceutically acceptable acid or anion exchange preparation, or the resulting salt can be converted into the corresponding acid addition salt, for example with a strong base, such as a metal or ammonium hydroxide, or with a base. This can be converted by salts such as alkali metal hydroxides or carbonates or by cation exchange preparations. These or other salts,
For example, picrate can also be used for purification of the base obtained. In view of the close relationship between the free compounds and the compounds in the form of their salts, compounds in this sense also include the corresponding salts. However, such a thing is possible or appropriate under the given circumstances.
それ等の塩を含む化合物も又それ等の水和物の形態で得
られ或いは結晶に対し用いられる他の溶剤も含むことが
出来る。Compounds including their salts may also be obtained in the form of their hydrates or may include other solvents used for crystallization.
更に本発明は式■の化合物及びその医薬として許容され
得る非毒性の酸付加塩を哺乳動物において使用すること
に関し、或いは又医薬として、特に冑腸剤として、特に
下痢、潰瘍、腸の炎症疾患及び脱水を含む胃腸分泌疾患
の治療に対し胃腸抗分泌剤としての医薬に関する。The present invention further relates to the use of the compound of formula (1) and its pharmaceutically acceptable non-toxic acid addition salts in mammals, or alternatively as a medicament, especially as a medicament, especially for diarrhea, ulcers, inflammatory diseases of the intestines. and medicaments as gastrointestinal antisecretory agents for the treatment of gastrointestinal secretory diseases including dehydration.
本発明は又医薬組成物、特に胃腸の抗分泌医薬組成物、
更にコルモソユリン抑制作用を有する抗下痢医薬組成物
の調製に対する本発明の化合物の使用に、も関する。The present invention also provides pharmaceutical compositions, particularly gastrointestinal antisecretory pharmaceutical compositions,
It further relates to the use of the compounds of the invention for the preparation of antidiarrheal pharmaceutical compositions having colmosoulin inhibiting action.
本発明に係る医薬組成物は、経口又は直腸の如き経腸に
対し、或いは経皮用に適した組成物であり、これは式Ｉ
の薬理的に活性な化合物の有効量又はその医薬として許
容され得る塩を巣独で又は一種又は二種以上の医薬とし
て許容され得る担体と共に含んでなる。The pharmaceutical composition according to the present invention is a composition suitable for oral or enteral administration, such as rectal administration, or transdermal administration, and is a composition suitable for oral administration, rectal administration, or transdermal administration.
alone or together with one or more pharmaceutically acceptable carriers.
本発明の医薬としての活性な化合物は、医薬組成物の製
造において有用であり、これは経腸又は経皮的適用のい
ずれかに対し適当な賦形剤又は担体と組み合わせて或い
は混合してその有効量を含んでなる。錠剤又はゼラチン
カプセル剤が好ましく、これ等は有効成分と共にａ）希
釈剤、例えばラクトース、テキシトロース、シュクロー
ス、マニトール、ソルビトール、セルロース及び／又は
グリシン；ｂ）潤滑剤、例えばシリカ、タルク、ステア
リン酸又はそのマグネシウム又はカルシウム塩、及び／
又はポリエチレングリコール；錠剤に対しては又Ｃ）結
合剤、例えば珪酸アルミニウムマグネシウム、澱粉ペー
スト、ゼラチン、トラがカント、メチルセルロース、カ
ルがキシメチルセルロースナトリウム及び／又はポリビ
ニルピロリドン；所望により、ｄ）崩壊剤、例えば澱粉
、寒天、アルギン藪又はそのナトリウム塩、又は発泡性
混合物；及び／又はｅ）吸着剤、着色剤、芳香剤及び甘
味剤を含んでなる。注入可能な組成物は、好ましくは水
性等張溶液又は懸濁液、及び半開は好都合には脂肪エマ
ルション又は懸濁液から好都合に調製される。これ等の
組成物は滅菌され及び／又は補助剤１例えば保存剤、安
定化剤、湿潤もしくは乳化剤、溶解促進剤、浸透圧調整
用の塩及び／又は緩衝剤を含有出来る。加えて、組成物
は又他の医薬として価値ある物質を含有することも出来
る。この組成物は、通常の混合、粒状化又はコーチング
法にそれぞれ従って調製され、有効成分を約０．１〜７
５チ、好ましくは約１〜５０％を含有する。The pharmaceutically active compounds of the invention are useful in the preparation of pharmaceutical compositions, which may be used in combination or admixture with suitable excipients or carriers for either enteral or transdermal application. comprising an effective amount. Preference is given to tablets or gelatin capsules, which contain together with the active ingredient a) diluents such as lactose, texitrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) lubricants such as silica, talc, stearic acid or its magnesium or calcium salt, and/or
or polyethylene glycol; for tablets also C) binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium caloxymethylcellulose and/or polyvinylpyrrolidone; optionally d) disintegrants; and/or e) adsorbents, colorants, fragrances and sweeteners. Injectable compositions are conveniently prepared from aqueous isotonic solutions or suspensions, and preferably from fatty emulsions or suspensions. These compositions may be sterilized and/or contain auxiliary agents such as preservatives, stabilizing agents, wetting or emulsifying agents, solubility promoters, salts for adjusting the osmotic pressure and/or buffering agents. In addition, the compositions can also contain other pharmaceutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1 to 7 ml of the active ingredient.
5%, preferably about 1-50%.
経皮適用に対し適尚な製剤は、有効量の式！の化合物と
共に担体を含む。好都合な担体には、ホストの皮膚を通
過させるのに役立つ吸収可能な医薬として許容され得る
溶剤が含まれる。特徴的には、経皮装置は背部材、所望
に工り担体と共に、所望により制御されかつ一定の速度
で長期間に亘ってホストの皮膚に化合物を放出する為の
速度調節バリヤと共に化合物を含有する容器並びに皮膚
に核装置を確保する為の手段を含んでなる帯具の形態に
ある。The formulation suitable for transdermal application is the formula of effective amount! The compound contains a carrier. Convenient carriers include absorbable pharmaceutically acceptable solvents that aid in passage through the skin of the host. Characteristically, the transdermal device includes a backing member, optionally along with an engineered carrier, containing the compound, optionally with a rate controlling barrier for releasing the compound into the host's skin at a controlled and constant rate over an extended period of time. It is in the form of a bandage comprising a container for holding the nuclear device and means for securing the nuclear device to the skin.
更に、本発明は又好都合にはコルモジ−リン阻害、特に
胃腸の分泌疾患例えば下痢、潰瘍、腸の炎症性疾患及び
脱水に対し応答し易い哺乳動物における疾患の治療方法
に関し、これは有効量の本発明化合物（式■又はその医
薬として許容され得る塩）、好ましくは上記医薬組成物
の形態で用いる。投与すべき有効化合物の量は、温血動
物（哺乳動物）の種、体重、年令及び個々の条件に依存
し更に投与形態に依存する。Furthermore, the present invention also advantageously relates to a method of treating gastrointestinal secretory diseases, such as diarrhea, ulcers, intestinal inflammatory diseases and diseases in mammals susceptible to dehydration, which advantageously involve colmodillin inhibition, which comprises the use of an effective amount of The compound of the present invention (formula (1) or a pharmaceutically acceptable salt thereof) is preferably used in the form of the above-mentioned pharmaceutical composition. The amount of active compound to be administered depends on the species of warm-blooded animal (mammal), body weight, age and individual condition, and also on the mode of administration.
約５０〜７０ｋｌ？の哺乳動物用の単位用量は、有効成
分を約５〜１００■含有する。Approximately 50-70kl? A unit dose for mammals contains about 5 to 100 μm of active ingredient.
次の実施例は本発明を例示するものであるが本発明はこ
れに限定されるものではない。温度は摂氏の単位で与え
られる。特に言及しガい限り、全ての蒸発は減圧下、特
に約１５〜１００ｗＨｇ の減圧下で行われる。最終生
成物、中間体及び出発物質の構造は元素分析、例えばミ
クロ分析及び光学分光特性値（例えばＩＲ、ＮＭＲ）に
より確認される。The following examples illustrate the invention, but the invention is not limited thereto. Temperature is given in degrees Celsius. Unless otherwise noted, all evaporations are performed under reduced pressure, particularly between about 15 and 100 wHg. The structure of the final products, intermediates and starting materials is confirmed by elemental analysis, eg microanalysis and optical spectroscopic properties (eg IR, NMR).
例１：１．３−ノヒドロー１−（１−［（４−メ□ チ
ル−４Ｈ，６Ｈ−ピｏｏ（１，２−−ａ）〔４，１〕−
ベンゾオキサゼピン−４−イ゛ル）−メチルツー４−ピ
ペリジニル）−２Ｈ一ヘンズイミダゾールー２−オンマ
レエート
１２０１１Ｌｌのテトラヒドロフランに懸濁させた３０
ｇの１，３−ジヒドロ−１−（１−［（４−メチル−４
Ｈ，６Ｈ−ピロロＣ１、２−ａ ） 〔４，１１ベンゾ
オキサゼピン−４−イル）−力ルぎニルツー４−ピペリ
ジニル）−２Ｉ（−ベンズイミダゾール−２−オンを、
７００＃の水素化アルミニウムリチウムを添加する。次
いで反応混合物を還流温度で６時間加熱し、引き続き室
温で１８時間攪拌する。反応混合物を１５０−のエーテ
ルで希釈し、次いで過剰の水素化アルミニウムリチウム
を以下に述べる通常の方法で破壊する。得られた粒状沈
殿物を濾過法により除去する。有機相を１５０ｍの希水
酸化す） ＩＪウムで洗浄し次いで１５０−のブライン
で洗浄する。有機抽出物を硫酸マグネシウムで乾燥し、
濾過し次いで溶剤を減圧下で除去し融点１９９〜２０１
℃を有する１、３−ジヒドロ−１−（１−（（４−メチ
ル−４Ｈ，６Ｈ−ピロロＣ１，２−ａ〕（４，１）ペン
ゾオキサゼピノー４−イル）−メチル〕−４−ピイリジ
ニル）−２Ｈ−ベンズイミダゾール−２−オン（式■（
式中Ｒ１及びＲ５が水素であり及びＲ２がメチルであり
更にｎが１である）の化合物）を得る。Example 1: 1.3-nohydro 1-(1-[(4-meth□ chill-4H,6H-pioo(1,2--a)[4,1]-
Benzoxazepine-4-yl)-methyl-4-piperidinyl)-2H-henzimidazole-2-one maleate 12,011 liters suspended in tetrahydrofuran
g of 1,3-dihydro-1-(1-[(4-methyl-4
H,6H-pyrroloC1,2-a) [4,11benzoxazepin-4-yl)-benzoxazepin-4-piperidinyl)-2I(-benzimidazol-2-one,
Add 700# lithium aluminum hydride. The reaction mixture is then heated at reflux temperature for 6 hours and subsequently stirred at room temperature for 18 hours. The reaction mixture is diluted with 150% ether and the excess lithium aluminum hydride is destroyed in the conventional manner described below. The resulting granular precipitate is removed by filtration. The organic phase is washed with 150 molar diluted hydroxide and then with 150 molar brine. The organic extract was dried with magnesium sulfate,
After filtration and removing the solvent under reduced pressure, the melting point was 199-201.
1,3-dihydro-1-(1-((4-methyl-4H,6H-pyrroloC1,2-a)(4,1)penzoxazepinol-4-yl)-methyl]-4 -pyridinyl)-2H-benzimidazol-2-one (formula ■(
A compound (in which R1 and R5 are hydrogen, R2 is methyl, and n is 1) is obtained.
次いで別々に遊離塩基とアセトンに溶解したマレイン酸
の当モル量を溶解し次いでその溶液を一緒にすることに
エリ該化合物のマレイン酸塩に該化合物を変換する。１
：１マレイン酸塩は放置することにエリ結晶化し融点１
８３〜１８５℃を有する。The compound is then converted to the maleate salt of the compound by separately dissolving the free base and equimolar amounts of maleic acid dissolved in acetone and then combining the solutions. 1
:1 Maleate crystallizes when left standing and has a melting point of 1.
It has a temperature of 83-185°C.
同様の方法にエリ調製した１：１フマール酸塩は融点１
２５〜１２７℃を有する。The 1:1 fumarate salt prepared in a similar manner has a melting point of 1
It has a temperature of 25-127°C.
出発化合物は次の如く調製する：
６７０ｄの氷酢酸に溶解した５００ｇのアントラニル酸
メチル及び４３８ｇの２．５−ジメトキシテトラヒドロ
フランの混合物を、還流温度で１．５時間加熱する。次
いで酢酸を減圧下で蒸発させ、残留物を希釈し沸点１０
９１０．１ 簡Ｈｇ の２−（ＩＨ−ビロール−１−イ
ル）−安息香酸メチルを得る。The starting compound is prepared as follows: A mixture of 500 g of methyl anthranilate and 438 g of 2,5-dimethoxytetrahydrofuran dissolved in 670 d of glacial acetic acid is heated at reflux temperature for 1.5 hours. The acetic acid is then evaporated under reduced pressure and the residue is diluted to a boiling point of 10
910.1 Hg of methyl 2-(IH-virol-1-yl)-benzoate is obtained.
２１の無水エーテルに懸濁させた（不活性雰囲気下）水
素化アルミニウムリチウム１１７ｇの懸濁液に１．５１
のエーテルに溶解した４２８ｇの２−（ピロロ−１−イ
ル）安息香酸メチルの溶液を４時間に亘って滴下する。In a suspension of 117 g of lithium aluminum hydride (under an inert atmosphere) in anhydrous ether of 1.51
A solution of 428 g of methyl 2-(pyrrolo-1-yl)benzoate dissolved in ether is added dropwise over a period of 4 hours.
次いで反応混合物を還流温度で更に４時間加熱し次いで
室温に冷却する。The reaction mixture is then heated at reflux for a further 4 hours and then cooled to room temperature.
水浴で冷却後、過剰の水素化アルミニウムリチウムを、
１１７ｍ１の水を１時間滴下して破壊し、引き続き１１
７ｄの１５チ水酸化ナトリウムを添加し更に引き続き３
５１ゴの水を３０分間添加する。After cooling in a water bath, remove excess lithium aluminum hydride.
Destroy by dropping 117ml of water for 1 hour, then continue to
Add 7d of 15-thiodium hydroxide and continue to add 3d of sodium hydroxide.
Add 51 tablespoons of water for 30 minutes.
得られた粒状固体を濾過法により分離し、エーテル層を
硫酸マグネシウムで乾燥し次いで減圧下で溶剤を除去し
２−（ピロール−１−イル）−ペンツルアルコールを得
、これは更に真空下で更に蒸留し沸点１１０〜１１４７
０．１ ｍＨｇ を得る。The resulting granular solid was separated by filtration, the ether layer was dried over magnesium sulfate and the solvent was removed under reduced pressure to yield 2-(pyrrol-1-yl)-pentyl alcohol, which was further purified under vacuum. Further distillation results in a boiling point of 110-1147
Obtain 0.1 mHg.
３００−の無水テトラヒドロフランに溶解した３４．６
ｇの２−（ピロロ−１−イル）−ベンジルアルコール及
び３２−のテトラメチルエチレンジアミン（ＴＭＥＤＡ
）の溶液に、反応の内部温度が３０゜以下に維持される
ように２１．４ モル溶液のれ一ブチルリチウム１
Ｂ ３ＷＬｌを添加する。添加終了後、反応混合物を室
温で３時間攪拌する。次いで反応混合物をドライアイス
／アセトン浴により一７０°に冷却し、次いで２４１ｎ
ｌのピルビン酸エチルを混合物に１分間添加する。次い
で混合物を室温に加温し次いで一夜（１８時間）攪拌す
る。次いで反応物を氷水／エーテル混合物に注ぎ侑様相
を分離し、硫酸マグネシウムで乾燥し次いで溶剤を減圧
下で蒸発させ融点９４〜９６°？：有するエチル４−メ
チル−４Ｈ，６Ｈ−ピロロ〔１，２−ａ）［４，１）ベ
ンゾオキサゼピン−４−カルがキシレートを得、これを
エーテル−ヘキサン（１：１）の混合物から再結晶する
。300-34.6 dissolved in anhydrous tetrahydrofuran
g of 2-(pyrrolo-1-yl)-benzyl alcohol and 32-tetramethylethylenediamine (TMEDA)
), add 21.4 molar solution of 1 mol of butyllithium so that the internal temperature of the reaction is maintained below 30°.
B Add 3WLl. After the addition is complete, the reaction mixture is stirred at room temperature for 3 hours. The reaction mixture was then cooled to -70° with a dry ice/acetone bath and then heated to 241 nm.
1 of ethyl pyruvate is added to the mixture for 1 minute. The mixture is then warmed to room temperature and stirred overnight (18 hours). The reaction was then poured into an ice water/ether mixture to separate the phase, dried over magnesium sulfate and the solvent was evaporated under reduced pressure, mp 94-96°? : Ethyl 4-methyl-4H,6H-pyrrolo[1,2-a)[4,1)benzoxazepine-4-cal with xylate obtained from a mixture of ether-hexane (1:1) recrystallize.
該化合物４１ｇ、３Ｎ水酸化ナトリウム１８０−及びエ
タノール１５０ｄの混合物を、還流温度で６時間加熱す
る。次いでエタノールを減圧下で蒸発により除去し次い
で水溶液を６ Ｎ ＨＣｌでｐＨ５に酸性化する。生成
物、融点１８２〜１８３°の４−メチル−４Ｈ，６Ｈ−
ビｏｏ（１，２−ａ）〔４，１〕ベンゾオキサゼピン−
４−カルぎン酸を濾過法により集め、次いで水性エタノ
ールから再結晶する。A mixture of 41 g of the compound, 180 g of 3N sodium hydroxide and 150 d of ethanol is heated at reflux temperature for 6 hours. The ethanol is then removed by evaporation under reduced pressure and the aqueous solution is acidified to pH 5 with 6 N HCl. Product, 4-methyl-4H,6H-, melting point 182-183°
Bio(1,2-a)[4,1]benzoxazepine-
4-Carginic acid is collected by filtration and then recrystallized from aqueous ethanol.
３００−のテトラヒドロフランに溶解したこの化合物７
．５ｇの溶液に、５ｇの１，１′−力ルゴニルジイミダ
ゾールを添加し次いで得られた混合物を室温で１時間攪
拌する。この混合物に、５１１の１．３−ジヒドロ−１
−（４−ピペリジル）−２Ｈ−ベンズイミダゾール−２
−オンを添加し、次いで反応を還流温度で４８時間加熱
する。室温に冷却後、反応混合物を１５０ｄの氷水に注
ぎ次いで１５０１ｎｌの塩化メチレン中で抽出する。有
機抽出物を引き続き１５０ｄの炭酸ナトリウム溶液、１
５ ＱＩＲｌの水及び１５０ＷＬｌの希塩酸で洗浄し、
硫酸マグネシウムで乾燥し、濾過し、次いで溶剤を減圧
下で蒸発させ融点２０８〜２１０°を有する１、３−ジ
ヒドロ−１−（１−［（４−メチル−４Ｈ，６Ｈ−ビｏ
ｏ ［： １ ＊ ２− ａ ］ （４ｅ １ ：）
ベンゾオキサゼピン−４−イル）−力ルがニルシー４−
ピペリジニル））−２Ｈ−ベンズイミダゾール−２−オ
ンを得る。This compound 7 dissolved in 300-tetrahydrofuran
．． To 5 g of the solution 5 g of 1,1'-mergonyldiimidazole are added and the resulting mixture is stirred at room temperature for 1 hour. To this mixture, 511 1,3-dihydro-1
-(4-piperidyl)-2H-benzimidazole-2
-one is added and the reaction is then heated at reflux for 48 hours. After cooling to room temperature, the reaction mixture is poured into 150 d of ice water and extracted into 1501 nl of methylene chloride. The organic extract was subsequently treated with 150 d of sodium carbonate solution, 1
5 Wash with QIRl of water and 150WLl of diluted hydrochloric acid,
Dry over magnesium sulfate, filter, and then evaporate the solvent under reduced pressure to obtain 1,3-dihydro-1-(1-[(4-methyl-4H,6H-bio
o [: 1 * 2- a ] (4e 1:)
benzoxazepine-4-yl)
piperidinyl))-2H-benzimidazol-2-one is obtained.
例２：１，３，４．５−テトラヒドロ−１−、（１−〔
（４−メチル−４Ｈ，６Ｈ−ピロロ〔１，２−ａ〕−［
：４．１］ベンゾオキサゼピン−４−イル）メチルツー
４−ピペリジニル）−２Ｈ−イミダゾール−２−オン
５０−のメタノールに溶解した４、５ｇの４−ホルミル
−４−メチル−４Ｈ，６Ｈ−ピロロ［１，２−ａ］（４
，１）ベンゾオキサゼピンの溶液に、３、６ ｍｌの５
．５Ｎメタノール性塩酸及び３．４ｇの１．３．４．５
−テトラヒドロ−１−（４−ピペリジニル）−２Ｈ−イ
ミダゾール−２−オンを添加し、引き続き９００１ｎ９
のナトリウムシアノゴロヒドリドを添加する。反応混合
物を室温で８日間攪拌する。２ｄの濃塩酸を反応混合物
に添加し次いで溶剤を減圧下で蒸発にエリ除去する。残
留物を１５０−の水中で溶解し次いで１：１酢酸エチル
−エーテル混合物１５０ｄで洗浄する。水相を分離し、
希水酸化ナトリウムでｐＨ９に塩基性化し次いで酢酸エ
チル１５０−で２回抽出する。−緒にした酢酸エチル抽
出液を無水硫酸マグネシウムで乾燥し、濾過し次いで溶
剤を減圧下で蒸発させ１．３．４．５−テトラヒドロ−
１−（１−［（４−メチル−４Ｈ，６Ｈ−ピロロ（１，
２−ａ）〔４，１〕ベンゾオキサゼピン−４−イル）−
メチル〕−４−ピペリジン−イル）−２Ｈ−イミダゾー
ル−２−オンを得、これはそのマレイン酸塩として融点
１９７〜１９９℃を有する。Example 2: 1,3,4.5-tetrahydro-1-, (1-[
(4-methyl-4H,6H-pyrrolo[1,2-a]-[
:4.1] benzoxazepin-4-yl)methyl-4-piperidinyl)-2H-imidazol-2-one 50- of 4.5 g of 4-formyl-4-methyl-4H,6H- dissolved in methanol. pyrrolo[1,2-a](4
,1) Into the solution of benzoxazepine, add 3.6 ml of 5
．． 5N methanolic hydrochloric acid and 3.4 g of 1.3.4.5
-tetrahydro-1-(4-piperidinyl)-2H-imidazol-2-one followed by 9001n9
of sodium cyanogolohydride. The reaction mixture is stirred at room temperature for 8 days. 2d of concentrated hydrochloric acid is added to the reaction mixture and the solvent is removed by evaporation under reduced pressure. The residue is dissolved in 150 g of water and washed with 150 g of a 1:1 ethyl acetate-ether mixture. Separate the aqueous phase;
Basify to pH 9 with dilute sodium hydroxide and extract twice with 150 ml of ethyl acetate. - The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered and the solvent was evaporated under reduced pressure to 1.3.4.5-tetrahydro-
1-(1-[(4-methyl-4H,6H-pyrrolo(1,
2-a) [4,1]benzoxazepin-4-yl)-
Methyl]-4-piperidin-yl)-2H-imidazol-2-one is obtained, which as its maleate salt has a melting point of 197-199°C.
出発物質は次のように調製する：
２００１ｎｌの塩化メチレンに溶解した７、０ｇのエチ
ル４−メチル−４Ｈ，６Ｈ−ピロロ−〔１，２−ａ）（
４，１）ベンゾオキサゼピン−４−カルがキシレート（
調製に対し例１を参照）の溶液を、−６５°に冷却し次
いで塩化メチレンに溶解した６５ｍＪの１．Ｏｍのジイ
ソブチルアルミニウムヒドリドを３０分に亘って添加す
る。添加終了後、反応物を一６０°で３０分間攪拌し、
引き続き反応混合物をメタノールで急冷する。次いで水
を添加し、冷却浴をとり除く。反応混合物を室温に至ら
しめ、次いで１５分間攪拌する。固形物を濾過法により
除去し次いで塩化メチレン溶液を無水硫酸マグネシウム
で乾燥し次いで溶剤を減圧下で蒸発させ油状生成物を得
、これはエーテルから結晶化させ融点８３〜８５℃を有
する４−ホルミル−４−メチル−４Ｈ，６Ｈ−ピロロ［
１，２−ａ］〔４，１〕ペングオキサゼピンを得る。The starting material is prepared as follows: 7.0 g of ethyl 4-methyl-4H,6H-pyrrolo-[1,2-a)(
4,1) Benzoxazepine-4-cal xylate (
For the preparation, see Example 1) solution was cooled to -65° and then dissolved in methylene chloride with 65 mJ of 1. Om diisobutylaluminum hydride is added over 30 minutes. After the addition was complete, the reaction was stirred at -60° for 30 minutes;
The reaction mixture is then quenched with methanol. Then water is added and the cooling bath is removed. The reaction mixture is allowed to reach room temperature and then stirred for 15 minutes. The solids were removed by filtration and the methylene chloride solution was dried over anhydrous magnesium sulphate and the solvent was evaporated under reduced pressure to give an oily product which was crystallized from ether and had a melting point of 83-85°C. -4-methyl-4H,6H-pyrrolo[
1,2-a][4,1]penguoxazepine is obtained.
例３：先の実施例に記載した手順に従って以下のものが
得られる：
ａ）８−［：（４−メチル−４Ｈ，６Ｈ−ピロロ（１，
２−ａ）（”４．１］ベンゾオキサゼピン−４−イル）
−メチルツー１−フェニル−１，３，８−トリアザスピ
ロ［４、５］デカン−４−オン；ｂ）１−［（４−メチ
ル−４Ｈ，６Ｈ−ピロロ（１，２−ａ）（：４，１：］
］ベンゾオキサゼピンー４−イル−メチルツー４−ヒド
ロキシ−４−フエニルビペリソン１：１マレエート、
ｍ、ｐ、 １７５−１７７° ；
ｅ）１−［（４−メチル−４Ｈ，６Ｈ−ピロロ（１＊２
−ａ’）（４，１）ベンゾオキサゼピン−４−イル）−
メチル〕−４−ヒドロキシ−４−（ｐ−クロロフェニル
）−ピペリジン；ｄ）１−（：（４−メチル−４Ｈ，６
Ｈ−ピロロ［：１．２−ａ］［４，１）ペンダオキサゼ
ピン−４−イル）−メチルツー４−フエニルビ’うｙｙ
二塩酸塩、 ｍ、ｐ、 １５５−１５７° ；ｅ）１
−（（４−メチル−４Ｈ，６Ｈ−ピロロ（１，２−ａ〕
ｃ４．１）ベンゾオキサゼピン−４−イル）−メチルツ
ー４−フエニルピベリジン１：１マレエート、ｍ、ｐ、
１２９−１３１° ；ｆ）１−（（４−メチル−４Ｈ，
６Ｈ−ピロロ（４，２−ａ）［４，１）ベンゾオキサゼ
ピン−４−イル）−メチルツー４−フェニルピペラジン
１：１マレニー）ｅｍ、ｐ、１２８−１３０’ ：ｇ）
１．３−ヅヒドロ−１−（１−［：（８−クロロ−４−
メチル−４Ｈ，６Ｈ−ピロロ〔１，２−＆〕［”４．１
］−ベンゾオキサゼピン−４−イル）−メチルツー４−
ピペリジニル）−２Ｍ−ベンズイミダゾール−２−オン
。Example 3: Following the procedure described in the previous example the following is obtained: a) 8-[:(4-methyl-4H,6H-pyrrolo(1,
2-a) (“4.1]benzoxazepin-4-yl)
-Methyl2-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one;b) 1-[(4-methyl-4H,6H-pyrrolo(1,2-a)(:4, 1:]
] Benzoxazepin-4-yl-methyl-4-hydroxy-4-phenylbiperisone 1:1 maleate,
m, p, 175-177°; e) 1-[(4-methyl-4H,6H-pyrrolo(1*2
-a')(4,1)benzoxazepin-4-yl)-
methyl]-4-hydroxy-4-(p-chlorophenyl)-piperidine; d) 1-(:(4-methyl-4H,6
H-pyrrolo[:1.2-a][4,1)pendaoxazepin-4-yl)-methyl-4-phenylbi'yy
Dihydrochloride, m, p, 155-157°; e) 1
-((4-methyl-4H,6H-pyrrolo(1,2-a)
c4.1) Benzoxazepin-4-yl)-methyl-4-phenylpiveridine 1:1 maleate, m, p,
129-131°; f) 1-((4-methyl-4H,
6H-pyrrolo(4,2-a)[4,1)benzoxazepin-4-yl)-methyl-4-phenylpiperazine 1:1 Maleny) em, p, 128-130' :g)
1.3-duhydro-1-(1-[:(8-chloro-4-
Methyl-4H,6H-pyrrolo[1,2-&][”4.1
]-benzoxazepin-4-yl)-methyl2-4-
piperidinyl)-2M-benzimidazol-2-one.
例４：
Ａ）有効成分１０■を各々含有する１０．０００個の錠
剤の調製：
以下余白
処方：
１，３−ソヒドロー１−（１−
〔（４−メチル−４Ｉ（，６Ｈ−ピロ
ロ−（：１．２−ａ）［４，１：）ベンゾオキサゼピン
−４−イル）−メチ
ルヨー４−ピペリジニル）−２Ｈ−
ベンズイミダゾール−２−オン１：１
マレエート １００．００
ｇラクトース ２，４００．
００ ｇコーンスターチ １２５
．００ ｇぼりエチレングリコール６，０００ １
５０．ＯＯＦステアリン酸マグネシウム
４０．００ ／ｉ蒸留水
適量手順：
全ての粉末を篩の目０．６ｍ＋を有するスクリーンを通
過させる。次いで薬物、ラクトース、ステアリン酸マグ
ネシウム及び澱粉の半量を適量な混合機内で混合する。Example 4: A) Preparation of 10,000 tablets each containing 10 μ of active ingredient: The following blank formulation: 1,3-Sohydro-1-(1-[(4-methyl-4I(,6H-pyrrolo-( :1.2-a) [4,1:)Benzoxazepin-4-yl)-methylio4-piperidinyl)-2H-benzimidazol-2-one 1:1 Maleate 100.00
g lactose 2,400.
00 g cornstarch 125
．． 00g ethylene glycol 6,000 1
50. OOF Magnesium Stearate
40.00/i distilled water
Dosing Procedure: Pass all the powder through a screen with a mesh size of 0.6 m+. The drug, lactose, magnesium stearate and half of the starch are then mixed in a suitable mixer.
澱粉の他の半量を６５１ｒＬｌの水に懸濁させ次いで懸
濁液’５７２６０１＋１１の水に溶解したポリエチレン
グリコールの沸騰溶液に添加する。得られたペーストを
粉末に添加し、粒状化し、必要により水を更に加える。The other half of the starch is suspended in 651 rLl of water and then added to a boiling solution of polyethylene glycol dissolved in suspension '572601+11 water. The resulting paste is added to the powder and granulated, adding more water if necessary.
粒状物を３５°で一夜乾燥し、篩目１．２ ｍを有する
スクリーン上で破壊し次いで上部が二等分した凹パンチ
を用い錠剤に圧縮する。The granules are dried overnight at 35°, broken on a screen with a mesh size of 1.2 m and compressed into tablets using a concave punch with a bisected top.
Ｂ）１０■の有効成分を各々含有する１、０００個のカ
プセル剤の調製：
処方：
１．３−ジヒドロ−１−（１−
〔（４−メチル−４Ｈ，６Ｈ−ピロ
ロ−［１，２−ａ）（４，１）ベン
ゾオキサゼピン−４−イル）−メチ
ルヨー４−ピペリジニル）−２Ｉ（−
ベンズイミダゾール−２−オン１：１
リレエート １０．００
ｇラクトース ２０７．０
０ｇ改質スターチ ｓ ｏ、ｏ
ｏ ｇステアリン酸マグネシウム ３．
００ ｇ手順：
全ての粉末を篩目０．６ｍを有するスクリーンを通過さ
せる。次いで薬物を適当な混合機内に装入し次いでステ
アリン酸マグネシウムでまず混合し、次いで均質になる
までラクトース及び澱粉と混合する。Ａ２硬ゼラチンカ
プセルを、カプセル充填機を用いて各々該混合物３００
■で充填する。B) Preparation of 1,000 capsules each containing 10 μ active ingredient: Formula: 1,3-dihydro-1-(1-[(4-methyl-4H,6H-pyrrolo-[1,2 -a) (4,1)benzoxazepin-4-yl)-methylio4-piperidinyl)-2I(-benzimidazol-2-one 1:1 lyleate 10.00
g lactose 207.0
0g modified starch s o, o
o g Magnesium stearate 3.
00 g Procedure: Pass all the powder through a screen with a mesh size of 0.6 m. The drug is then charged into a suitable mixer and mixed first with magnesium stearate and then with lactose and starch until homogeneous. A2 hard gelatin capsules were each filled with 300 g of the mixture using a capsule filling machine.
Fill with ■.
本明細書及び不実施例で説明した他の化合物約５〜１０
０■を含有する同様の錠剤及びカプセル剤を特徴するAbout 5 to 10 other compounds described herein and in non-examples
Characterized by similar tablets and capsules containing 0■
Claims (1)
素、低級アルキル、ハロゲン、トリフルオロメチル、ヒ
ドロキシもしくは低級アルコキシを表わし；Ｒ＿２は水
素又は低級アルキルを表わし；Ｒ＿３は水素、低級アル
キル又はハロゲンを表わし；Ｒ＿４はアミノ、低級アル
キルアミノ、ジ−低級アルキルアミノ、モルホリノ、Ｎ
−低級アルキルもしくはＮ−アリール−ピペラジノ、ピ
ロリジノ、ピペリジノ又は ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼および ▲数式、化学式、表等があります▼ （前記式中、Ｒ＿５は水素、ハロゲン又は低級アルキル
を表わす）から選ばれる置換ピペリジノを表わす） で表わされる化合物およびその塩。 ２、前記式 I 中、ｎが１又は２であり；Ｒ＿４が特許
請求の範囲第１項で定義された置換ピペリジノを表わす
、特許請求の範囲第１項記載の化合物又はその医薬とし
て許容され得る塩。 ３、次式II： ▲数式、化学式、表等があります▼（II） （Ｒ＿１は水素、低級アルキル、ハロゲン、トリフルオ
ロメチル、ヒドロキシ又は低級アルコキシを表わし；Ｒ
＿２は水素又は低級アルキルを表わし；ｎは整数１〜４
を表わし；更にＲ＿５は水素、ハロゲン又は低級アルキ
ルを表わす） で表わされる化合物である特許請求の範囲第１項記載の
化合物、又はその医薬として許容され得る塩。 ４、前記式II中、ｎが整数１又は２であり；Ｒ＿２が直
鎖の低級Ｃ＿１＿〜＿４アルキルであり；Ｒ＿１及びＲ
＿５が水素又はハロゲンを表わす、特許請求の範囲第３
項記載の化合物、又はその医薬として許容され得る塩。 ５、前記式II中、Ｒ＿１及びＲ＿５は水素を表わし、Ｒ
＿２はメチルを表わし；更にｎが整数１である、特許請
求の範囲第３項記載の化合物又はその医薬として許容さ
れ得る塩。 ６、１，３−ジヒドロ−１−｛１−〔（４−メチル−４
Ｈ，６Ｈ−ピロロ〔１，２−ａ〕〔４，１〕ベンゾオキ
サゼピン−４−イル）−メチル〕−４−ピペリジニル｝
−２Ｈ−ベンズイミダゾール−２−オンである特許請求
の範囲第１項記載の化合物及びその医薬として許容され
得る塩。 ７、特許請求の範囲第１項〜第６項のいずれかに記載の
化合物と共に一種又はそれ以上の医薬として許容され得
る担体を含んでなる医薬組成物。 ８、ヒト又は動物の治療方法に用いられる特許請求の範
囲第１項〜第６項のいずれかに記載の化合物。 ９、抗下痢剤として使用される特許請求の範囲第１項〜
第６項のいずれかに記載の化合物。 １０、胃腸剤として使用される特許請求の範囲第１項〜
第６項のいずれかに記載の化合物。 １１、医薬組成物の製造に使用される特許請求の範囲第
１項〜第６項のいずれかに記載の化合物の使用。 １２、ａ）次式III： Ｒ＿４−Ｈ（III） （式中、Ｒ＿４は特許請求の範囲第１項で定義した意味
と同じであり、さらに水素は該基Ｒ＿４のアミノ窒素に
結合している） で表わされるアミンを、次式IV： ▲数式、化学式、表等があります▼（IV） （式中、ｎ、Ｒ＿１、Ｒ＿２およびＲ＿３は特許請求の
範囲第１項で定義した意味と同じであり、さらにＸは反
応性エステル化ヒドロキシを表わす）で表わされる化合
物と縮合させるか、又は次式Ｖ：▲数式、化学式、表等
があります▼（Ｖ） （式中、ｎ、Ｒ＿１、Ｒ＿２およびＲ＿３は先に定義し
た意味と同じである） で表わされる化合物と還元的アミノ化の条件下で縮合さ
せるか、又は ｂ）次式VI： ▲数式、化学式、表等があります▼（VI） （式中、ｎおよびＲ＿１〜Ｒ＿４は特許請求の範囲第１
項で定義した意味と同じである） で表わされる化合物を還元し；次いで前記プロセスを行
い、この間必要ならば全てのこれらのプロセス中防害性
反応基を保護し、次いで得られた式 I の化合物を本発
明の他の化合物に変換し、および／又は所望により得ら
れた遊離化合物を塩に変換するか又は得られた塩を遊離
化合物もしくは他の塩に変換するか、および／又は、所
望により得られた異性体又はラセミ体混合物を個々の異
性体又はラセミ体に分離し、および／又は得られたラセ
ミ体を光学対掌体に分割することを特徴とする、特許請
求の範囲第１項記載の化合物の製造方法。 １３、次式IV： ▲数式、化学式、表等があります▼（IV） （式中、ｎは整数１、２、３、又は４であり；Ｒ＿１は
水素、低級アルキル、ハロゲン、トリフルオロメチル、
ヒドロキシ又は低級アルコキシを表わし；Ｒ＿２は水素
又は低級アルキルを表わし；Ｒ＿３は水素、低級アルキ
ル又はハロゲンを表わし；更にＸはヒドロキシを表わす
） で表わされる化合物。 １４、式Ｖ： ▲数式、化学式、表等があります▼（Ｖ） （式中ｎは整数１、２、３又は４を表わし；Ｒ＿１は水
素、低級アルキル、ハロゲン、トリフルオロメチル、ヒ
ドロキシ又は低級アルコキシを表わし；Ｒ＿２は水素又
は低級アルキルを表わし；Ｒ＿３は水素、低級アルキル
又はハロゲンを表わす）で表わされる化合物。 １５、式IX： ▲数式、化学式、表等があります▼（IX） （式中ｎは整数１、２、３又は４を表わし；Ｒ＿１は水
素、低級アルキル、ハロゲン、トリフルオロメチル、ヒ
ドロキシ又は低級アルコキシを表わし；Ｒ＿２は水素又
は低級アルキルを表わし；Ｒ＿３は水素、低級アルキル
又はハロゲンを表わす）で表わさせる化合物又はそのエ
ステル。 １６、式VI： ▲数式、化学式、表等があります▼（VI） （式中ｎは整数１、２、３又は４を表わし；Ｒ＿１は水
素、低級アルキル、ハロゲン、トリフルオロメチル、ヒ
ドロキシ又は低級アルコキシを表わし；Ｒ＿２は水素又
は低級アルキルを表わし；Ｒ＿３は水素、低級アルキル
又はハロゲンを表わし；Ｒ＿４はアミノ、低級アルキル
アミノ、ジ−低級アルキルアミノ、モルホリノ、Ｎ−低
級アルキルもしくはＮ−アリール−ピペラジノ、ピロリ
ジノ、ピペリジノ又は ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼、 ▲数式、化学式、表等があります▼、▲数式、化学式、
表等があります▼及び ▲数式、化学式、表等があります▼（前記全ての基中Ｒ
＿５は水素、 ハロゲン又は低級アルキルを表わす）から選ばれる置換
ピペリジノを表わす） で表わされる化合物。[Claims] 1. The following formula I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, n is an integer 1, 2, 3, or 4; R_1 is hydrogen, lower alkyl, halogen , trifluoromethyl, hydroxy or lower alkoxy; R_2 represents hydrogen or lower alkyl; R_3 represents hydrogen, lower alkyl or halogen; R_4 represents amino, lower alkylamino, di-lower alkylamino, morpholino, N
-Lower alkyl or N-aryl-piperazino, pyrrolidino, piperidino or ▲Mathematical formulas, chemical formulas, tables, etc.▼, ▲mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
Compounds represented by the following formulas ▼ and ▲ mathematical formulas, chemical formulas, tables, etc. 2. In the formula I, n is 1 or 2; R_4 represents a substituted piperidino as defined in claim 1, or a pharmaceutically acceptable compound thereof according to claim 1 salt. 3. The following formula II: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) (R_1 represents hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy or lower alkoxy; R
_2 represents hydrogen or lower alkyl; n is an integer 1 to 4
and R_5 represents hydrogen, halogen or lower alkyl), or a pharmaceutically acceptable salt thereof. 4. In the formula II, n is an integer 1 or 2; R_2 is a linear lower C_1_-_4 alkyl; R_1 and R
Claim 3, in which _5 represents hydrogen or halogen
A compound as described in Section 1, or a pharmaceutically acceptable salt thereof. 5. In the above formula II, R_1 and R_5 represent hydrogen, and R
_2 represents methyl; further, n is an integer 1, or a pharmaceutically acceptable salt thereof according to claim 3. 6,1,3-dihydro-1-{1-[(4-methyl-4
H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl)-methyl]-4-piperidinyl}
A compound according to claim 1 which is -2H-benzimidazol-2-one and a pharmaceutically acceptable salt thereof. 7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 and one or more pharmaceutically acceptable carriers. 8. A compound according to any one of claims 1 to 6 for use in a method of treating humans or animals. 9. Claims 1 to 9 used as anti-diarrheal agents
A compound according to any of paragraph 6. 10. Claims 1 to 1 for use as a gastrointestinal agent
A compound according to any of paragraph 6. 11. Use of the compound according to any one of claims 1 to 6 for use in the manufacture of a pharmaceutical composition. 12, a) The following formula III: R_4-H(III) (wherein R_4 has the same meaning as defined in claim 1, and further hydrogen is bonded to the amino nitrogen of the group R_4 ) The amine represented by the following formula IV: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (wherein, n, R_1, R_2 and R_3 have the same meaning as defined in claim 1). and furthermore, X represents a reactive esterified hydroxyl) or condensed with a compound represented by the following formula V: ▲ Numerical formula, chemical formula, table, etc. ▼ (V) (where n, R_1, R_2 and R_3 has the same meaning as defined above) or b) under reductive amination conditions with the compound represented by the following formula VI: ▲Mathematical formula, chemical formula, table, etc. In the formula, n and R_1 to R_4 are defined in claim 1.
the compound of the formula converting the compound into other compounds of the invention and/or optionally converting the resulting free compound into a salt or converting the resulting salt into the free compound or other salt; Claim 1, characterized in that the isomer or racemic mixture obtained by is separated into individual isomers or racemates and/or the racemate obtained is resolved into optical antipodes. Method for producing the compound described in Section 1. 13. The following formula IV: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) (In the formula, n is an integer 1, 2, 3, or 4; R_1 is hydrogen, lower alkyl, halogen, trifluoromethyl,
hydroxy or lower alkoxy; R_2 represents hydrogen or lower alkyl; R_3 represents hydrogen, lower alkyl or halogen; and X represents hydroxy). 14, Formula V: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) (In the formula, n represents an integer 1, 2, 3, or 4; R_1 is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, or lower alkoxy; R_2 represents hydrogen or lower alkyl; R_3 represents hydrogen, lower alkyl or halogen). 15, Formula IX: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IX) (In the formula, n represents an integer 1, 2, 3, or 4; R_1 is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, or lower alkoxy; R_2 represents hydrogen or lower alkyl; R_3 represents hydrogen, lower alkyl or halogen; or an ester thereof. 16, Formula VI: ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the formula, n represents an integer 1, 2, 3, or 4; R_1 is hydrogen, lower alkyl, halogen, trifluoromethyl, hydroxy, or lower represents alkoxy; R_2 represents hydrogen or lower alkyl; R_3 represents hydrogen, lower alkyl or halogen; R_4 represents amino, lower alkylamino, di-lower alkylamino, morpholino, N-lower alkyl or N-aryl-piperazino , pyrrolidino, piperidino or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ mathematical formulas, chemical formulas,
There are tables, etc. ▼, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, ▲ Mathematical formulas, chemical formulas,
There are tables, etc. ▼ and ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (all of the above groups R
_5 represents a substituted piperidino selected from hydrogen, halogen, or lower alkyl).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/821,110 US4758559A (en) | 1986-01-21 | 1986-01-21 | Pyrrolo[1,2-a] [4,1]benzoxazepine derivatives useful as calmodulin and histamine inhibitors |
| US821110 | 1986-01-21 |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5324407A Division JPH0826028B2 (en) | 1986-01-21 | 1993-12-22 | Pyrrolo [1,2-a] [4,1] benzoxazepine derivative |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS62169791A true JPS62169791A (en) | 1987-07-25 |
| JPH0780888B2 JPH0780888B2 (en) | 1995-08-30 |
Family
ID=25232538
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62009181A Expired - Fee Related JPH0780888B2 (en) | 1986-01-21 | 1987-01-20 | Pyrrolo [1,2-a] [4,1] benzoxazepine derivative |
| JP5324407A Expired - Lifetime JPH0826028B2 (en) | 1986-01-21 | 1993-12-22 | Pyrrolo [1,2-a] [4,1] benzoxazepine derivative |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP5324407A Expired - Lifetime JPH0826028B2 (en) | 1986-01-21 | 1993-12-22 | Pyrrolo [1,2-a] [4,1] benzoxazepine derivative |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US4758559A (en) |
| EP (1) | EP0233483B1 (en) |
| JP (2) | JPH0780888B2 (en) |
| KR (1) | KR900004148B1 (en) |
| AT (1) | ATE62244T1 (en) |
| AU (1) | AU598510B2 (en) |
| CA (1) | CA1273335A (en) |
| CY (1) | CY1749A (en) |
| DD (1) | DD257430A5 (en) |
| DE (1) | DE3768978D1 (en) |
| DK (1) | DK169239B1 (en) |
| ES (1) | ES2039363T3 (en) |
| FI (1) | FI86636C (en) |
| GR (1) | GR3001737T3 (en) |
| HK (1) | HK24194A (en) |
| HU (1) | HU198061B (en) |
| IE (1) | IE59653B1 (en) |
| IL (1) | IL81302A (en) |
| MA (1) | MA20857A1 (en) |
| MY (1) | MY100914A (en) |
| PH (1) | PH25148A (en) |
| PT (1) | PT84136B (en) |
| TN (1) | TNSN87003A1 (en) |
| ZA (1) | ZA87389B (en) |
| ZW (1) | ZW787A1 (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SG48855A1 (en) * | 1992-04-20 | 1998-05-18 | Takeda Chemical Industries Ltd | 4,1-benzoxazepin derivatives and their use |
| US5452434A (en) * | 1992-07-14 | 1995-09-19 | Advanced Micro Devices, Inc. | Clock control for power savings in high performance central processing units |
| US5321012A (en) * | 1993-01-28 | 1994-06-14 | Virginia Commonwealth University Medical College | Inhibiting the development of tolerance to and/or dependence on a narcotic addictive substance |
| USRE39300E1 (en) | 1993-01-28 | 2006-09-19 | Virginia Commonwealth University Medical College Of Virginia | Inhibiting the development of tolerance to and/or dependence on an addictive substance |
| US5439524A (en) * | 1993-04-05 | 1995-08-08 | Vlsi Technology, Inc. | Plasma processing apparatus |
| US5698518A (en) * | 1994-03-30 | 1997-12-16 | Oklahoma Medical Research Foundation | Method for regulating inflammation and tumor growth with calmodulin, calmodulin analogues or calmodulin antagonists |
| US5624902A (en) * | 1995-06-07 | 1997-04-29 | Torrey Pines Institute For Molecular Studies | Peptide inhibitors of calmodulin |
| US6423329B1 (en) | 1999-02-12 | 2002-07-23 | The Procter & Gamble Company | Skin sanitizing compositions |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4029672A (en) * | 1976-02-26 | 1977-06-14 | American Hoechst Corporation | Aminoalkylpyrrolobenzoxazalkanes |
| US4053599A (en) * | 1976-02-26 | 1977-10-11 | American Hoechst Corporation | Piperazionalkylpyrrolobenzoxazalkanes |
| US4045448A (en) * | 1976-02-26 | 1977-08-30 | American Hoechst Corporation | Pyrrolo[2,1-c][1,4]benzoxazepine and benzoxazocine derivatives |
| US4169095A (en) * | 1977-01-19 | 1979-09-25 | American Hoechst Corporation | Process for preparing aminoalkylpyrrolobenzoxazalkanes |
| US4608374A (en) * | 1983-11-07 | 1986-08-26 | Hoechst-Roussel Pharmaceuticals Inc. | 11-substituted 5H,11H-pyrrolo[2,1-c][1,4]benzoxazepines as antipsychotic and analgesic agents |
-
1986
- 1986-01-21 US US06/821,110 patent/US4758559A/en not_active Expired - Lifetime
-
1987
- 1987-01-05 MY MYPI87000013A patent/MY100914A/en unknown
- 1987-01-14 PH PH34722A patent/PH25148A/en unknown
- 1987-01-19 IL IL81302A patent/IL81302A/en not_active IP Right Cessation
- 1987-01-19 DD DD87299332A patent/DD257430A5/en unknown
- 1987-01-19 FI FI870207A patent/FI86636C/en not_active IP Right Cessation
- 1987-01-19 PT PT84136A patent/PT84136B/en unknown
- 1987-01-19 ES ES87100598T patent/ES2039363T3/en not_active Expired - Lifetime
- 1987-01-19 CA CA000527583A patent/CA1273335A/en not_active Expired - Lifetime
- 1987-01-19 DE DE8787100598T patent/DE3768978D1/en not_active Expired - Lifetime
- 1987-01-19 AT AT87100598T patent/ATE62244T1/en not_active IP Right Cessation
- 1987-01-19 EP EP87100598A patent/EP0233483B1/en not_active Expired - Lifetime
- 1987-01-20 ZW ZW7/87A patent/ZW787A1/en unknown
- 1987-01-20 HU HU87152A patent/HU198061B/en not_active IP Right Cessation
- 1987-01-20 ZA ZA87389A patent/ZA87389B/en unknown
- 1987-01-20 AU AU67813/87A patent/AU598510B2/en not_active Ceased
- 1987-01-20 JP JP62009181A patent/JPH0780888B2/en not_active Expired - Fee Related
- 1987-01-20 DK DK029587A patent/DK169239B1/en not_active IP Right Cessation
- 1987-01-20 MA MA21090A patent/MA20857A1/en unknown
- 1987-01-20 IE IE13987A patent/IE59653B1/en not_active IP Right Cessation
- 1987-01-20 TN TNTNSN87003A patent/TNSN87003A1/en unknown
- 1987-01-21 KR KR1019870000454A patent/KR900004148B1/en not_active IP Right Cessation
-
1991
- 1991-04-04 GR GR91400317T patent/GR3001737T3/en unknown
-
1993
- 1993-12-22 JP JP5324407A patent/JPH0826028B2/en not_active Expired - Lifetime
-
1994
- 1994-03-17 HK HK241/94A patent/HK24194A/en not_active IP Right Cessation
- 1994-06-03 CY CY174994A patent/CY1749A/en unknown
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